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Stroke Research & Clinical Trials

Clinical Trials

The NINDS conducts stroke research and clinical trials at its laboratories and clinics at the NIH, and through grants to major medical institutions across the country.

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The Carotid Revascularization Endarterectomy vs Stenting Trial (CREST) was designed to compare the safety and efficacy of two stroke prevention procedures—carotid endarterectomy (CEA) and carotid artery stenting (CAS). Over the course of the nine year trial, more than 2,500 patients were randomized in 117 sites in the United States and Canada to receive one of the two procedures, and evaluated 30 days and up to four years later for the occurrence of a stroke, a heart attack or death, as well as other complications. The study, funded by the National Institutes of Health, was the first large-scale effort to compare the two procedures in both symptomatic and asymptomatic patients. Symptomatic patients were those who had experienced a minor stroke or a warning sign of stroke indicating a high risk for future stroke. The symptomatic patients had a blockage (stenosis) in the carotid artery of 50 percent or greater, measured by angiography. Asymptomatic patients are at much lower natural risk of stroke, even with substantial carotid blockage, than those with symptoms.

Stenting versus Endarterectomy for Treatment of Carotid-Artery Stenosis - published in NEJM May 26, 2010 — CREST-2 is a national multicenter stroke prevention study that is actively enrolling participants with narrowing in their carotid artery without stroke or stroke warning signs (TIAs or mini-strokes) caused by that artery for a research study. The study is comparing intensive medical management alone to intensive medical management used in combination with a procedure to remove plaque buildup from the carotid artery in the neck. For more information:

Stroke is a leading cause of death in the United States and the leading cause of adult disability. Each year 800,000 people experience a new or recurrent stroke, at an estimated cost of $69.9 billion in direct and indirect costs according to a 2010 report.

There are two types of stroke:  ischemic, caused by a clot that creates a blockage of blood flow to the brain, and hemorrhagic, caused by bleeding in or around the brain. Ischemic strokes are far more common, 87 percent compared to 13 percent hemorrhagic.

Ischemic strokes are often caused by stenosis, or narrowing of the carotid artery due to the buildup of cholesterol in the wall of the artery (called atherosclerotic plaque). The degree of stenosis is usually expressed as a percentage of the normal diameter of the vessel. Major stroke due to carotid disease is usually caused by a clot which forms in the narrowed artery and then travels into the brain.

Atherosclerosis is a vascular disease in which deposits of plaque buildup along the artery walls and causes stenosis, decreasing blood flow. Atherosclerosis in the carotids, two large arteries on each side of the neck that serve as the major source of blood flow to the brain and eye, is a major risk factor for ischemic stroke. Because persons with atherosclerosis in the carotids usually also have atherosclerosis in the coronary arteries that supply the heart, the CREST study tracked heart attacks as well as stroke and death.

What are the warning signs of stroke?

Many patients develop warning signs of stroke such as short episodes of loss of vision in the eye on the side of the diseased carotid, transient numbness or weakness on the face or hand, or episodes of inability to speak. These warning signs of impending stroke may only last for a minute or two and require immediate medical attention.

What is a carotid endarterectomy?

A carotid endarterectomy (CEA) is a procedure in which a neurosurgeon or vascular surgeon removes atherosclerotic plaque from one of the two carotid arteries in order to prevent stroke. The procedure is usually conducted under general anesthesia. Two large clinical trials supported by the National Institute of Neurological Disorders and Stroke (NINDS) have compared the surgery against standard medical therapy (treatment with aspirin, and blood pressure and cholesterol lowering drugs) in asymptomatic and symptomatic patients.

  • In 1991, the North American Symptomatic Carotid Endarterectomy Trial (NASCET) found that surgery for symptomatic patients with severe stenosis of 70 percent or greater dramatically reduced their high risk of stroke or death over a two-year period, from greater than 1 in 4 to less than 1 in 10.
  • In 1994, the Asymptomatic Carotid Atherosclerosis Study (ACAS) showed that CEA surgery lowered the five-year risk of stroke by about one-half, from greater than 1 in 10 to less than 1 in 20 in asymptomatic patients with stenosis of 60 percent or greater. To show benefit in asymptomatic patients, the stroke/death risk of having the procedure needs to be below about three percent and the expected life span of greater than five years.

In both studies, the medical expertise of the surgeons was carefully controlled in centers and was limited to physicians who had performed a series of successful CEAs. Although carotid endarterectomies have been performed since the 1950s, these two trials provided patients and physicians with definitive information for making decisions about stroke prevention treatment.

What is carotid artery stenting?

During carotid artery stenting (CAS), an interventionalist inserts a stent into the carotid artery using angioplasty, in which a catheter with an attached balloon is inserted into a small incision over an artery in the groin. The catheter is guided to the blockage site using x-ray imaging. At the blockage site, the physician inflates the angioplasty balloon to flatten the plaque and widen the space through which the blood flows. After the artery is open, the physician removes the catheter with the balloon attached and guides a compressed stent to the same area. The stent then expands to widen the artery. The stent holds the artery open by holding back the flattened plaque. The stents used in the CREST trial included an embolic protection device--a basket, or filter designed to catch pieces of the fractured atherosclerotic plaque that may break away during the procedure. Stents, which are made of stainless steel or metal alloys, remain permanently in the carotid artery. The patient is generally conscious during the procedure.

CAS was introduced in the 1990s and was approved by the FDA in 2004 for use in patients who were considered too high-risk to undergo carotid surgery. In 2005 the Centers for Medicare & Medicaid Services (CMS) approved reimbursement for high-risk symptomatic stroke patients. CMS has reimbursed for CEA for many years.

What are the complications of each procedure?

After both procedures there is a small risk of heart attack or stroke because of the disruption of the plaque, which can send clots into the bloodstream. The basket in the stenting procedure is intended to prevent this from happening. In CAS, there is also the possibility of a blood clot forming along the stent or a tear in the artery wall called a dissection.

In both procedures, there is also the possibility that the carotid artery will become blocked again over time, called restenosis.

What types of medical professionals perform these procedures?

CEAs are generally performed by vascular surgeons and neurosurgeons, and CAS can be performed by interventionalists who include vascular surgeons, radiologists, vascular neurologists, neurointerventionalists, neuroradiologists and cardiologists. The interventionalists who participated in the CREST trial were required to perform a series of successful procedures in order to participate in the study. This occurred during a lead-in phase of 1,500 patients. The surgeons qualified if they had performed a minimum of 50 CEAs, which were reviewed prior to their approval for participation in the trial.

How many procedures are performed annually?

In 2006, a total of 99,000 CEAs and 23,000 CAS procedures were performed in the U.S. [Sources: Circulation, Vol. 119, pp. e21-e181; Abbott.]  

What are the costs for each procedure? 

According to the 2006 Medicare Fee Schedule, physicians were paid about $1,100 for performing CEA, and just less than $1,100 for performing CAS. The diagnosis-related group (DRG) payment to hospitals performing uncomplicated CEA was $4,600, while hospitals performing uncomplicated CAS received almost $6,000. The cost of a stent and embolic protection system was an additional $3,000, approximately. [Source: Changes in the Use of Carotid Revascularization Among the Medicare Population, Archives of Surgery, Volume 143, No. 2, Feb. 2008.]

What is the average length of hospital stay for each procedure?

Generally, CEA patients spend two days in the hospital whereas the average length of time for CAS patients is roughly a day and a halfor less.  

What was the cost of the study?

NINDS provided a total of $23,807,271 to support the study. Partial funding was provided by Abbott, of Abbott Park, Ill., the maker of the stents and embolic protection systems used in the trial.

How common is carotid artery disease?

With age, people tend to have more plaque buildup in their arteries which can be caused by high cholesterol, diabetes and smoking. By some estimates, 25 percent of strokes are caused by carotid artery disease.

How is carotid artery disease diagnosed?

In some cases, carotid artery disease can be detected during a routine checkup when a physician hears the sound of turbulent blood flow with a stethoscope on the neck. In others, there may be imaging tests required. In the CREST trial, two imaging techniques were used:

Ultrasound imaging--This is a noninvasive test in which sound waves above the range of human hearing are sent into the neck. Echoes bounce off the moving blood and the tissue in the artery and can be formed into an image that shows the degree of blockage in the arteries.

Magnetic Resonance Angiography (MRA)--This is an imaging technique that uses magnetic fields to create an image of the bloodflow in the carotid arteries. Sometimes contrast agents are injected into the veins to achieve a clearer image.

Computer Tomography Angiography (CTA)--This is an imaging technique that uses x-rays to image the blood vessel after a contrast agent is injected into a vein in the arm.

What do the CREST results tell us?

The overall safety and efficacy of the two procedures was largely the same, with equal benefit for both men and for women, and for patients who had previously had a stroke and for those who had not. However, when the investigators looked at the numbers of heart attacks and strokes, they found differences.  There were more heart attacks in the surgical group, 2.3 percent compared to 1.1 percent in the stenting group; and more strokes in the stenting group, 4.1 percent versus 2.3 percent for the surgical group in the weeks following the procedure.

The study also found that the age of the patient made a difference. At approximately age 69 and younger, stenting results were slightly better, with a larger benefit for stenting, the younger the patient. Conversely, for patients older than 70, surgical results were slightly superior to stenting, with larger benefits for surgery, the older the age of the patient.

Long-term followup will provide more information on health-related quality of life measures, cost, and a further information about the specific factors that made a difference in the patient's outcome after the procedure.

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